Research work has established that in most tissues the major product of the arachiodonic acid metabolism is either of two unstable substances, thromboxane A.sub.2 (TxA.sub.2) or prostacyclin (PGI.sub.2). (Proc. Nat. Acad. Sci. U.S.A., 1975, 72, 2294, Nature, 1976, 263, 663, Prostaglandins, 1976. 12, 897). In most cases the prostaglandins PGE.sub.2, PGF.sub.2 and PGD.sub.2 are comparatively minor by-products in this biosynthetic pathway. The discovery of thromboxane A.sub.2 and prostacyclin has significantly increased out understanding of vascular homeostasis, prostacyclin for instances is a powerful vasodilator and inhibitor of platelet aggregation, and in this last respect is the most potent endogenous substance so far discovered. The prostacyclin synthetase enzyme is located in the endothelial layer of the vasculature, and is fed by endoperoxides released by blood platelets coming into contact with the vessel wall. The prostacyclin thus produced is important for prevention of platelet deposition on vessel walls. (Prostaglandins, 1976, 12, 685, Science, 1976, 17, Nature, 1978, 273, 765).
Thromboxane A.sub.2 is synthesised by the thromboxane synthetase enzyme which is located in, for example, the blood platelets. Thromboxane A.sub.2 is a powerful vasoconstrictor and pro-aggregatory substance. As such its actions are in direct opposition to those of prostacyclin. If, for any reason, prostacyclin formation by the vasculature is impaired, then the endoperoxides produced by platelets coming into contact with the vessel wall are converted into thromboxane, but are not converted effectively into prostacyclin (Lancet, 1977, 18, Prostaglandins, 1978, 13, 3). Alteration of the prostacyclin/thromboxane balance in favour of the latter substance could result in platelet aggregation, vasospasm (Lancet, 1977, 479, Science, 1976, 1135, Amer. J. Cardiology, 1978, 41, 787) and an increased susceptibility to atherothrombosis (Lancet (i) 1977, 1216). It is also known that in experimental atherosclerosis prostacyclin ganeration is suppressed and thromboxane A.sub.2 production is enhanced (Prostaglandins, 1977, 14, 1025 and 1035). Thus thromboxane A.sub.2 has been implicated as the causative agent in variant angina, myocardial infarction, sudden cardiac death and stroke (Thromb. Haemostasis, 1977, 38, 132). Studies in rabbits have shown that ECG changes typical of these conditions were produced when freshly prepared thromboxane A.sub.2 was injected directly into the animal's heart (Biochem. aspects of Prostaglandins and Thromboxanes, Editors, N. Kharasch and J. Fried, Academic Press 1977 page 189). This technique is considered to represent a unique animal model of the heart attacks of coronary patients and has been used to show that administration of a compound believed to antagonise the effects of thromboxane A.sub.2 protects the rabbits from the adverse consequences of thromboxane A.sub.2 injection.
Another area where a PGI.sub.2 /TxA.sub.2 imbalance is considered to be a contributory factor is that of migraine.
The migraine headache is associated with changes in intra and extracerebral blood flow, in particular a pre-headache reduction of cerebral blood flow followed by dilatation in both vascular areas during the headache phase.
Prior to the development of the headache, blood levels of 5-hydroxytryptamine are elevated, and this suggests the occurrence of in vivo aggregation and release of the amine from the platelet stores. It is known that the blood platelets of migraine patients are more prone to aggregate than are those of normal individuals (J. Clin. Pathol., 1971, 24, 250, J. Headache, 1977, 17, 101). Furthermore, it has now been postulated that not only is an abnormality of platelet function a major factor in the pathogenesis of migraine attacks but it is in fact their prime cause (Lancet (i), 1978, 501). Thus a drug that selectively modifies platelet function to inhibit thromboxane A.sub.2 formation could be of considerable benefit in migraine therapy.
Abnormalities of platelet behaviour have been reported in patients with diabetes mellitus (Metabolism, 1979, 28, 394, Lancet, 1978, (i) 235). Diabetic patients are known to be particularly susceptible to microvascular complications, atherosclerosis and thrombosis and platelet hyper-reactivity has been suggested as the cause of such angiopathy. Diabetic platelets produce elevated amounts of TxB.sub.2 and malondialdehyde (Symposium "Diabetes and Thrombosis - Implications for Therapy," Leeds U.K., April 1979). Also it has been shown that in rats with experimental diabetes vascular prostacyclin production is impaired and TxA.sub.2 synthesis from the platelets is elevated (IV International Prostaglandin Conference, Washington, D.C. May 1979). Thus the imbalance between prostacyclin and TxA.sub.2 is considered to be responsible for the microvascular complications of diabetes. A TxA.sub.2 -synthetase inhibitor could therefore find clinical utility in preventing these vascular complications.
Aspirin and most other non-steroidal anti-inflammatory drugs inhibit the cyclo-oxygenase enzyme. The effect of this is to shut down the production of the PGG.sub.2 /H.sub.2 endoperoxides and by so doing to reduce both the prostacyclin and thromboxane A.sub.2 levels. Aspirin and aspirin-like drugs have been evaluated clinically for prevention of stroke and heart attack (New England and J. Med. 1978, 299, 53, B.M.J., 1978, 1188, Stroke, 1977, 8, 301).
Although some encouraging results have been obtained with these drugs, a compound which specifically inhibits thromboxane A.sub.2 formation leaving the biosynthesis of prostacyclin unimpaired would be more valuable in these clinical conditions (Lancet (ii), 1978, 780).
The ability of primary neoplasms to metastasize is a principal cause of failure to cure human cancers. It has been suggested that metastatic tumour cells can alter the critical PGI.sub.2 -TxA.sub.2 balance in favour of thrombosis (Science, 1981, 212, 1270). Prostacyclin has recently been shown to be a powerful anti-metastatic agent by virtue of its platelet anti-aggregatory action. This result indicates that a TxA.sub.2 -synthetase inhibor may function as an anti-metastatic agent in vivo (J. Cell. Biol. 1980, 87 64).
U.K. patent application No. 2045244A claims selective thromboxane synthetase inhibitors of the formula: ##STR1## These compounds differ substantially from the present compounds.
A publication in Eur. J. Med. Chem.--Chimica Theropeutica, May-June 1975, vol. 10, No. 3, p. 276-285 discloses antiinflammatory antiarthritic and fibrinolytic agents of the formula: ##STR2## and related compounds.